Endoplasmic reticulum (ER) is a key organelle fundamental for the maintenance of cellular homeostasis and for determination of cell fate under stress conditions. Among the proteins known to regulate ER structure and function is reticulon-1C (RTN-1C), a member of the reticulon family proteins localized primarily on the ER membrane. Previous studies suggested that RTN-1C is able to trigger ER stress-induced cell death, although the exact mechanism still remains unclear.
Based on these findings, here I have further investigated the impact of RTN-1C overexpression on Ca2+ signaling and mitochondrial dynamics in human neuroblastoma cell line. When transiently overexpressed, RTN-1C is linked to disruption of intracellular Ca2+ homeostasis, Ca2+-dependent autophagy and mitochondrial elongation. Conversely, RTN-1C mediated prolonged ER-stress was able to induce over time mitochondrial fragmentation and cell death. Importantly, neuronal loss was rescued by the novel JNK inhibitor D-JNKI1, supporting a crucial role for this pathway in RTN-1C induced apoptosis. These in vitro data were then supported by in vivo evidence obtained on a transgenic mouse overexpressing RTN-1C. This model displayed alterations in the expression profile of specific genes and neurodegenerative features in the cerebral cortex.
Overall, this work defines a role for RTN-1C as a potential molecular target for use in therapy and as a specific marker for neurological/neurodegenerative diseases.